{"doi":"10.1016/j.celrep.2024.114964","title":"HIRA protects telomeres against R-loop-induced instability in ALT cancer cells","abstract":"Inactivating mutations in chromatin modifiers, like the α-thalassemia/mental retardation, X-linked (ATRX)-death domain-associated protein (DAXX) chromatin remodeling/histone H3.3 deposition complex, drive the cancer-specific alternative lengthening of telomeres (ALT) pathway. Prior studies revealed that HIRA, another histone H3.3 chaperone, compensates for ATRX-DAXX loss at telomeres to sustain ALT cancer cell survival. How HIRA rescues telomeres from the consequences of ATRX-DAXX deficiency remains unclear. Here, using an assay for transposase-accessible chromatin using sequencing (ATAC-seq) and cleavage under targets and release using nuclease (CUT&RUN), we establish that HIRA-mediated deposition of new H3.3 maintains telomeric chromatin accessibility to prevent the detrimental accumulation of nucleosome-free single-stranded DNA (ssDNA) in ATRX-DAXX-deficient ALT cells. We show that the HIRA-UBN1/UBN2 complex deposits new H3.3 to prevent TERRA R-loop buildup and transcription-replication conflicts (TRCs) at telomeres. Furthermore, HIRA-mediated H3.3 incorporation into telomeric chromatin links productive ALT to the phosphorylation of serine 31, an H3.3-specific amino acid, by Chk1. Therefore, we identify a critical role for HIRA-mediated H3.3 deposition that ensures the survival of ATRX-DAXX-deficient ALT cancer cells.","journal":"Cell Reports","year":2024,"id":424385,"datarank":0.6472965352694302,"base_score":3.1354942159291497,"endowment":3.1354942159291497,"self_citation_contribution":0.47032413238937254,"citation_network_contribution":0.1769724028800576,"self_endowment_contribution":0.47032413238937254,"citer_contribution":0.1769724028800576,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":21,"citers_with_citation_signal":10,"citers_with_endowment":10,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.949,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE269261","GSE269268"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":235987,"name":"Emily Brown","orcid":"0000-0003-1073-4377","position":1,"is_corresponding":false},{"id":327756,"name":"Ragini Bhargava","orcid":null,"position":2,"is_corresponding":false},{"id":327758,"name":"Anne R. Wondisford","orcid":null,"position":3,"is_corresponding":false},{"id":1221343,"name":"Jean-Baptiste Ouriou","orcid":null,"position":4,"is_corresponding":false},{"id":1221344,"name":"Oliver Freund","orcid":null,"position":5,"is_corresponding":false},{"id":1221345,"name":"Ray E. Bowman","orcid":null,"position":6,"is_corresponding":false},{"id":1164627,"name":"Baylee A. Smith","orcid":null,"position":7,"is_corresponding":false},{"id":1047480,"name":"Santana M. Lardo","orcid":"0000-0003-0403-5326","position":8,"is_corresponding":false},{"id":1221346,"name":"Sandra Schamus-Hayes","orcid":null,"position":9,"is_corresponding":false},{"id":481137,"name":"Sarah J. Hainer","orcid":"0000-0003-0503-1183","position":10,"is_corresponding":false},{"id":326575,"name":"Roderick J. O’Sullivan","orcid":"0000-0002-0289-0911","position":11,"is_corresponding":false},{"id":326571,"name":"Michelle Lee Lynskey","orcid":"0000-0002-0343-3413","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T01:58:07.191194Z","pmid":"39509271","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}